Landiolol and Organ Failure in Patients With Septic Shock
Authors: Tony Whitehouse, Anower Hossain, Gavin D. Perkins, Anthony C. Gordon, Julian Bion, Duncan Young, Danny McAuley, Mervyn Singer, Janet Lord, Simon Gates, Tonny Veenith, Niall S. MacCallum, Joyce Yeung, Richard Innes, Ingeborg Welters, Nafisa Boota, Emma Skilton, Belinder Ghuman, Maddy Hill, Scott E. Regan, Dipesh Mistry, Ranjit Lall, Tonny Veenith, Jaimin Patel, Nick Murphy, Mansoor Bangash, Tomasz Torlinski, Nicholas Talbot, Catherine Snelson, Dhruv Parekh, Amisha Desai, Mary Kotada, Yin May Chin, Sophie Holden, Aoife Neal, Maximina Ventura, Martin Pope, Samantha Harkett, Christopher McGhee, Emma Fellows, Amy Bamford, Ronald Carrera, Karen Ellis, Elaine Spruce, Liesl Despy, Stephanie Porter, Colin Bergin, Stephanie Gouny, Hazel Smith, Tracy Mason, Natalie Dooley, Amy Clark, Joyce Yeung, Jo Gresty, Teresa Melody, Ellie Reeves, Rachel Smith, Julia Sampson, ACCP Team BHH Critical Care Unit, Chris Nutt, James Mcnamee, Danny Mcauley, Anen Boyle, Loren McGinley, Chris Wright, Kathryn Ward, Lauren Macartney, Justine Mccann, Brian Wells, Janette Mills, Leona Bannon, Aisling O’Neill, Stephanie Finn, Anthony Gordon, David Antcliffe, Stephen Brett, Dorota Banach, Leilani Cabreros, Laura Curran, Sonia Sousa Arias, Roceld Rojo, Ziortza Fernandez de Pinedo Artaraz, Phoebe Coghlan, Maie Templeton, Ahmed ElHaddad, Zohonon Sabine Loko, Gareth Barker, Niall MacCallum, David Brealey, Mervyn Singer, Kristian Warnes, Nina Bason, Dorota Filipowicz, Georgia Bercades, Ingrid Hass, Jung Ryu, Deborah Smyth, Dorothy Ilano, Dan Harvey, Louise Conner, Lucy Ryan, Cecilia Peters, Megan Meredith, Megan Mcaulay, Zoe Whitman, Lucy Morris, Claudia Woodford, Sally Hodgkinson, Sonya Finucane, Luigi Camporota, Manu Shankar-Hari, Marlies Ostermann, Aneta Bociek, Rosario Lim, Neus GrauNovellas, Natalie Palmer, Angela Cape, Anea Kelly, Gill Arbane, Sarah Campos, Michael Singh, Jinny Yoo, Richard Innes, Fiona Dempsey, Patricia Doble, Rebecca Purnell, Moira Tait, Jo Hutter, Corinne Pawley, Joy Rowe, Catherine Wane, Richard Burgess, Ashly Thomas, Pulak Paul, Brenda White, Wayne Lovegrove, Mandy Gill, Lynne Wade, Tracy Brear, Vishal Dhokia, Debbie Jackson, Sarah Shelton, Jill Kirk, Anew Boulton, Alistair Roy, Anthony Rostron, Zeynep Elcioglu, Lindsey Woods, Sarah Cornell, Rebecca Betts, Jill Holden, Stephen Laybourne, Kimberley Rogerson, Jeremy Bewley, Rebekah Johnson, Anna Chillingworth, Bethany Gumbrill, Hilary Galvin, Kim Wright, Georgia Efford, Kathleen Corcoran, Libby Cole, Katie Sweet, Denise Webster, Lisa Grimmer, Gemma Paris, Chloe Searles, Zoe Garland, Charly Gibson, Melanie Hutchings, Fiona Walters, Sinead Kelly, Lorraine Scaife, Kelly Littlewood, James Leavy, Shirley Todd, Elizabeth Gordon, Sadie Heddon, Victor Mariano, Karin Gupwell, Rebecca Appelboam, Samantha Keenan, Cassie Brady, Ian Mew, Duncan Chambler, Sarah Williams, Pauline Ashcroft, Patricia Williams, James Rees, Sophie Wiseman, Sarah Horton, Mark Shortland, Stephanie Dukes, Andy Ball, Michael Spivey, Jennie Stephens, Sarah Bean, Karen Burt, Rachel Chapman, Carol Richards, Lorraine Moore, Linda Allsop, Amber Wynn, Louise Latty, Sam Waddy, Kayleigh Spencer, Bethan Stowe, Georgina Cox, Helen McMillan, Liana Lankester, Colin Wells, Rosalyn Squire, Mike Marner, Robert Jackson, Nikitas Nikitas, Stuart Dickson, Henrik Reschreiter, James Bromilow, James Keegan, Chris Loew, Ken Power, Spike Briggs, Julie Camsooksai, Sarah Patch, Sarah Jenkins, Sharon Power, Elizabeth Woodward, David Pogson, Zoe Daly, Steve Rose, Aimi Collins, Amy Phelps, Helen Claridge, Christine Minnis, Sarah Inglis, Lutece Brimfield, Charlotte Wong, Ingeborg Welters, Karen Williams, Victoria Waugh, Julie Patrick-Heselton, Emily Johnson, David Shaw, Brian Johnston, Maryam Crews, Alicia Waite, Vinoth Sankar, Jonathan Walker, Peter Turton, Richard Wenstone, Jaime Fernandez Roman, Alison Hall, Maria Lopez Martinez, David Oliver Hamilton, David Coey, Philip Shelley, Martin Goulding, Karen Kavanagh, Ann Marron, Hannah Allsop, Phil Hopkins, John Smith, Harriet Noble, Evita Pappa, Clare Finney, Sinead Heyler, Emma Clarey, Maeve Cockrell, Maria Therese Depante, Kevin O'Reilly, Christopher Waterhouse, Vicky Chu, Joanne Gordon, Greg Marchant, Stuart Chandler, Senait Haile, Joanna Flanagan, Gaynor Notcheva, Dom Jimenez, Dilbagh Gill, Sunil Jamadarkhana, Sunita Gohil, Sura Dabbagh, Katy-Jane Chick, Carina Cruz, Vikram Anumakonda, Vanessa Moore, Lisa Stanton, Sharon Westwood, Jacqueline Smith, Karen Reid, Ranjit Gidda, Elena Anastasescu, Karim Salem, Mohamed Mooradun, Michael Reay, Nasirul Ekbal, Margaret McNeil, Helder Filipe, Aarti Nandani, Glykeria Pakou, Mark de Neef, Sara Mingo, Amitaa Maharajh, Prashanth Nandhabalan, Thomas Billyard, Laura Wild, Pamela Bremmer, Geraldine Ward, Fiona McGurk, Rajbinder Deol, Catherine Morgan, Kirandeep Pachoo, Barbara Phillips, Owen Boyd, Claire Phillips, Rakhee Hindocha, Stephen Age, John Porter, Alex Harrison, Lynn Evans, Louise Ortiz-Ruiz de Gordoa, Dominika Wlazly, Tomas Anews, Jess West, Ben Attwood, Paul Jefferson, Penny Parsons, Sophie Mason, Bridget Campbell, Julia Jones, Kathryn Webb, Karen Spicer, Angela Day, Camilla Stagg, Noor Ayesha Shah, Ian Purcell, Lucy Shafiq, Coralie Carle, Rebecca Chilvers, Heather MacColl, Alan Pope, Anew Holder, Nicola Butterworth-Cowin, Matthew Davies, Louise Wilmer, Nadeem Ismail, Sneha Gurung, Piers Murphy, Toby Elkington, Matthew Camilleri, Rob Charnock, Claire Shevlin, Emma McGregor, Chris Clarke, Judith Hinds, Sophie Hughes, Raymond McKee, Denise McFarland, Roisin McNulty, Andy Breen, Elizabeth Wilby, Nora Youngs, Richard French, Suzie Colquhoun, Claire Posnett, Clare Howcroft, Anew Taylor, Simon Whiteley, Bethan Ogg, Kate Long, Alicia Tomkinson, Ian Clement, Tara Shrestha, Leigh Dunn, Verity Calder, Maite Babio-Galan, Kimberley Zwiggelaar, Anne Mitchell, Julie Stephenson, Lesley Rigden, Jude Davison, Joseph Carter, Kate Howard, Hazel Cahill, Lia Grainger, Poppy Cottrell-Howe, Abigail Rowbotham, Laura Jeffery, Emily Waterman, Arran Fletcher, Zoe Guy, Isabel Birkinshaw, Jo Ingham, Zoe Scott, Samantha Stead, Raha West, Pradeep Shanmugasundaram, Judith Abrams, Geraldine Hambrook, Katarina Manso, Sally Scott, Iram Husain, Evelyn Chan, Siobhan Gettings, Anil Hormis, Rachel Walker, Dawn Collier, Cheryl Graham, Victoria Murray, Katy Curtis, Charlotte Widdop, Sarah Kimpton, Susan Oakley, Zirlish Afzal, James Varley, Petra Polgarova, Andrew Johnston, Lynne Whitehead, Andrew Conway Morris, Razeen Mahroof, Sofia Teixeira, Nazrudeen Ali, Jonny Wilkinson, Alex Lyon, Charlotte Mills, Kathryn Hall, Gayna Grantham, Lorraine Campey, Helen Cronshaw, Livia Malanjum, Lucy Dudgeon, Clare Hinchley, Stephen Langhon, Jane Hosea, Anea Hillyer, Rachel Kontogonis, Oninye Ndefo, Laura Robinson, Callum Kaye, Kevin Sim, Ian Scott, Teresa Scott, Felicity Anderson, Wendy Mitchell, Patricia Cooper, James MacBrayne, Fiona Willox, Kate Richmond, Rebecca Colleron, Erin Trumper, Bartosz Was, Michael Christie, Amber Johnson, Gillian Price, Malcolm Sim, Robert Docking, Scott McQueen, Sophie Kennedy-Kay, Lynn Abel, Steven Henderson, Kirsty McLeash, Anew Gratrix, Victoria Martinson, Louise Foster, Elizabeth Stones, Vicki Lowthorpe, Daniel Crawley, Susannah Leaver, Sarah Farnell Ward, Romina Pepermans Saluzzio, Frances Robinson, Carlos Delgado, Geraldine Gray, Rebecca Kanu, Robert Oakley, Karen M. Keates, Tim Walsh
Journal: JAMA (2023)

Importance Patients with septic shock undergo adrenergic stress, which affects cardiac, immune, inflammatory, and metabolic pathways. β-Blockade may attenuate the adverse effects of catecholamine exposure and has been associated with reduced mortality. Objectives To assess the efficacy and safety of landiolol in patients with tachycardia and established septic shock requiring prolonged (&amp;amp;gt;24 hours) vasopressor support. Design, Setting, and Participants An open-label, multicenter, randomized trial involving 126 adults (≥18 years) with tachycardia (heart rate ≥95/min) and established septic shock treated for at least 24 hours with continuous norepinephrine (≥0.1 μg/kg/min) in 40 UK National Health Service intensive care units. The trial ran from April 2018 to December 2021, with early termination in December 2021 due to a signal of possible harm. Intervention Sixty-three patients were randomized to receive standard care and 63 to receive landiolol infusion. Main Outcomes and Measures The primary outcome was the mean Sequential Organ Failure Assessment (SOFA) score from randomization through 14 days. Secondary outcomes included mortality at days 28 and 90 and the number of adverse events in each group. Results The trial was stopped prematurely on the advice of the independent data monitoring committee because it was unlikely to demonstrate benefit and because of possible harm. Of a planned 340 participants, 126 (37%) were enrolled (mean age, 55.6 years [95% CI, 52.7 to 58.5 years]; 58.7% male). The mean (SD) SOFA score in the landiolol group was 8.8 (3.9) compared with 8.1 (3.2) in the standard care group (mean difference [MD], 0.75 [95% CI, −0.49 to 2.0]; P = .24). Mortality at day 28 after randomization in the landiolol group was 37.1% (23 of 62) and 25.4% (16 of 63) in the standard care group (absolute difference, 11.7% [95% CI, −4.4% to 27.8%]; P = .16). Mortality at day 90 after randomization was 43.5% (27 of 62) in the landiolol group and 28.6% (18 of 63) in the standard care group (absolute difference, 15% [95% CI, −1.7% to 31.6%]; P = .08). There were no differences in the number of patients having at least one adverse event. Conclusion and Relevance Among patients with septic shock with tachycardia and treated with norepinephrine for more than 24 hours, an infusion of landiolol did not reduce organ failure measured by the SOFA score over 14 days from randomization. These results do not support the use of landiolol for managing tachycardia among patients treated with norepinephrine for established septic shock. Trial Registration EU Clinical Trials Register Eudra CT: 2017-001785-14 ; isrctn.org Identifier: ISRCTN12600919